Systems and methods relating to medical applications of synthetic polymer formulations

ABSTRACT

Systems, methods and compositions relating to delivering synthetic polymer formulations to the body are described, which can be used by a range of medical personnel including those with minimal experience and training. Under some embodiments, the present invention relates to systems and devices for delivering polymer formulations to a body cavity (e.g. peritoneal cavity) to reduce or stop bleeding. Under some embodiments, an initial percutaneous access pathway is first formed using a delivery device with a probe and needle mechanism that automatically stops the advance of the device upon insertion into a body cavity or space, thus minimizing user error and improving patient safety. The hollow probe then allows transmission of polymer, mixed with gas and/or additional substances, from a holding chamber or canister to flow through the device and hollow probe into the patient&#39;s anatomic cavity or space of interest, stopping expansion when the device senses the appropriate pressure. Once reaching the body cavity, the polymer formulation functions to reduce and/or stop bleeding.

RELATED APPLICATIONS

The present application claims the benefit of U.S. ProvisionalApplication No. 62/643,846 filed Mar. 16, 2018, which is herebyincorporated herein in its entirety by reference.

U.S. patent application Ser. No. 13/961,422, filed Aug. 7, 2013 andentitled Method and Device for Simultaneously Documenting and TreatingTension Pneumothorax and/or Hemothorax and U.S. patent application Ser.No. 14/581,339, filed Dec. 23, 2014 and entitled Percutaneous ChannelSystem and Method, and U.S. patent application Ser. No. 17/961,422,filed Sep. 22, 2017 and titled Percutaneous Access Pathway System, allhaving at least one of the same inventors, are hereby incorporated byreference herein in their entirety.

FIELD OF THE INVENTION

The present disclosure relates generally to the medical field, and moreparticularly, to systems and methods relating to the medicalapplications of synthetic polymer formulations. In one application, thepresent invention relates to systems and devices for deliveringresorbable synthetic polymer formulations to the body.

BACKGROUND OF THE INVENTION

A wide variety of diagnostic and/or therapeutic procedures involve thedelivery of synthetic polymers to the body. One objective is to providehemostasis of bleeding vessels and other organs. This bleeding may beinternal or external in nature and from all sites on the body. Anotherobjective is to provide the delivery of pharmaceutical agents (e.g.hemostatic agents, antibiotics, anesthetics). This delivery may be toall sites on the body, internal or external.

A recent review of U.S. battlefield deaths from 2001-2011 demonstratedthat around 90% of all injury mortality occurred in the pre-medicaltreatment facility environment. Of the potentially survivable deaths,the vast majority were due to hemorrhage (90%), with the bleeding comingin order of frequency from the abdominopelvic, thoracic, junctional,extremity areas.

Internal bleeding (e.g. abdominopelvic and thoracic) is particularlydifficulty to stop without highly specialized care facilities. Civilianstudies have found that for major traumatic injuries in the abdomen, theprobability of death increases approximately 1% for each 3-minute delayto surgery. American military experts have declared that the inabilityto stop intra-abdominal bleeding quickly in the field “signifies a clearand persistent gap in medical treatment capability that has been presentfor the entire history of warfare and well documented for nearly acentury.”

The gold standard for severe traumatic intra-abdominal bleeding isemergent laparotomy, which requires the lengthy training and perishableskills of a trauma surgeon, as well as a sterile operating room. As themajority of the U.S. combat deaths are in the pre-medical treatmentfacility environment, reducing them requires a technology that personnelwith limited training can deploy rapidly, in the out-of-hospital orin-hospital environments.

The literature discloses various known systems and methods related todelivering hemorrhage control to the body.

For example, U.S. Pat. No. 8,828,050 B2 to Gregory et al. describes anapplicator for delivering a plurality of sponges capable of expandingupon contact with a liquid to a body cavity. Related product informationfrom RevMedx, Inc. regarding their Xstat products describe hemostaticdevices for the treatment of gunshot and shrapnel wounds that work byinjecting a group of small, rapidly-expanding sponges into woundcavities using a syringe-like applicator. In the wound, the spongesexpand and swell to fill the wound cavity to create a temporary barrierto blood flow and provide hemostatic pressure. However, this system isnot ideally set up to inject sponges throughout the abdominal cavity. Italso can only access the abdominal cavity through an existingpenetrating trauma wound, therefore making it of little use in thesetting of blunt abdominal trauma.

U.S. Patent Publication Nos. 2011/0202016 A1 to Zugates et al. and2012/0107439 A1 to Sharma et al. (with related U.S. Patent PublicationNos. 2013/0110066 A1 to Sharma et al.; 2012/0265287 A1 to Sharma et al.;2009/0041824 A1 to Zugates et al.; and, 2016/0271293 A1 to Zugates etal.) describe injecting a biodegradable synthetic polymer into a bodycavity together with another agent; the polymer and other agent thensubsequently combine via a chemical reaction within the body cavity toproduce a hardened elastomeric polymer foam, which prevents or limitsbleeding. Product information from Arsenal Medical describes a hardeningfoam that binds to intra-abdominal tissues to reduce and stop bleeding.The provider injects two liquid polymers from a canister, via a largenaked needle, into the abdominal cavity. Upon combination inside, theseingredients react to envelop and harden around the internal organs.

However, a solidified product in the abdominal cavity may cause seriousmedical issues for the life of the patient. Likewise, needing to cut outa large block of hardened material after use is clearly suboptimal.Additionally, the prior art does not include any safety method formedics or others in the out-of-hospital environment to deploy asynthetic polymer intra-abdominally, except for a naked needle.Insertion of a large naked needle into the abdomen, even by highlytrained surgeons in a controlled operating room environment, can easilyresult in bowel or other intra-abdominal injury. Thus, this method isclearly suboptimal.

U.S. Patent Publication Nos. 2014/0271531 A1, 2014/0316012 A1,2013/0317418 A1, and 2014/0271533 A1 to Freyman et al. describeinjection of prepolymer that reacts with water to cause an in-situforming polymer foam for embolizing or occluding cavities (e.g.aneurysm, lung, vessel). However, this also becomes a hard foam that isnot easily reversible. It also must react with water within the body,which may result in variable response depending on the dampness of thatparticular body cavity. It is further described for injection intosmaller lumen cavities and not those with very large volumes, such asthe peritoneal cavity. U.S. Patent Publication No. 2002/0122771 A1 toHolland et al. shows a wound dressing hydrogel that can be sprayed on asa liquid and then crosslink or otherwise thicken to form a hydrogel insitu with similar limitations.

U.S. Pat. No. 8,668,899 B2 to Dowling et al. describes a sprayablepolymeric foam hemostat for both compressible and non-compressible(intracavitary) acute wounds. This foam comprises ahydrophobically-modified polymer (e.g. hm-chitosan) or relatedamphiphilic polymers that anchor themselves within the membrane of cellsin the vicinity of the wound. However, this polymer is not easily washedaway and needs to be broken down before excretion from the body.Chitosan and related substances are additionally not syntheticallyformulated, which may lead to quality control issues and difficulty inmanufacturing. Finally, this product and related hemostatic foams do nothave a means for inducing physical tamponade within the body from thecontrollable transmission of higher pressures.

Prior art includes multiple uses of polymers for hemostasis. Theseinclude examples of gels, putties, and waxes to assist with tamponade ofbleeding. Examples include U.S. Pat. No. 8,497,408 B2 to Winek et al.U.S. Patent Publication Nos. 2004/0013715A1 to Winek et al.,2003/0095945 A1 to Levey et al., 2006/0100370 A1 to Wellisz et al.,2009/0286886 A1 to Fisher et al., 2006/0193899 A1 Sawhney, 2016/0256170A1 to Busold et al., 2003/0203044 A1 to Moravec, and U.S. Pat. No.9,616,088 B2 to Diehn et al. However, these polymers are directlyapplied to the site of injury and do not foam to be sprayed on or spreadthroughout a body cavity.

The literature additionally discloses prior art regarding inversethermosensitive polymers (i.e. inverse or reverse thermosensitive,thermosetting, phase, or thermally viscosifying polymers) as a means ofproviding hemostasis. Several publications describe use of inversethermosensitive polymers to provide temporary embolization of a vesselvia intravascular gel injection, such as U.S. Patent Publication No.2005/0008610 A1 to Schwarz et al., 2005/0147585 A1 to Schwarz,2011/0087207 A1 to Vogel et al, and 2008/0181952 A1 to Vogel et al.However, these do not spread via foam to provide hemostasis throughout alarger area and volume. Similarly, U.S. Patent Publication No.2007/0191768 A1 to Kolb (with related U.S. Pat. No. 8,062,282) providesa method for occluding a body lumen by placing the tip of a catheterinto a lumen, spraying thermosensitive polymer, and then withdrawing thetip. However, this requires at least partial withdrawal of the cathetertip while spraying directly in the area of interest. Likewise, U.S.Patent Publication No. 2008/0208163 A1 to Wilkie discloses the use of aninverse thermosensitive polymer to control biological fluid flow by anin situ formed polymer plug. However, this gel or solution also needs tobe directly injected through a catheter to a specific site.Additionally, U.S. Patent Publication No. 2008/0031847 A1 to Cohn et al.(with related U.S. Patent Publication No. 2013/0158589) describes amethod and kit for treating lacerations and puncture wounds using aninverse thermosensitive polymer. However, this polymer does not foam andis rather a liquid that becomes a gel after spraying it from a syringeor tube. These are thus not amenable to spread throughout a larger areaor volume (e.g. via injection into a large body cavity, such as theperitoneal cavity).

The prior art additionally discloses multiple uses of inversethermosensitive polymers for the delivery of different pharmaceuticalagents, although not specifically utilized with foam delivery. Theseinclude U.S. Pat. No. 4,474,752 to Haslam et al. and 6,316,011 B1 to Ronet al., and U.S. Patent Publication No. 2011/0294760 A1 to Bahulekar etal.

Each of the patents and published patent applications mentioned aboveare hereby incorporated by reference.

SUMMARY OF THE INVENTION

The present invention overcomes and substantially alleviates thedeficiencies in the prior art by providing improved systems and methodsrelating to synthetic polymer formulations.

In several embodiments, the present invention relates to systems anddevices for delivering synthetic polymers to a body cavity (e.g.abdominal cavity) to reduce and/or stop bleeding. Under some of theseembodiments, the synthetic polymer formulation may be provided in theform of an aqueous solution, gel, or foam. In some of these embodiments,the synthetic polymer formulation can be cleared by the body, such thatthere is no need for subsequent physical removal (e.g. resorbable).

In several embodiments, emergency personnel can rapidly deploy thesystem to deliver polymer formulation to the body to reduce or stopbleeding in the out-of-hospital or in-hospital environments, includingunder battlefield and mass casualty conditions.

Under some embodiments, the polymer may be used externally. Under otherembodiments, an initial percutaneous access pathway into a body cavityis surgically established (e.g. laparotomy trocar, open surgicalprocedure) and connected to a delivery apparatus. Under otherembodiments, an initial percutaneous access pathway is formed similar tothe device and/or method described in U.S. patent application Ser. Nos.13/961,422 and 14/581,339, previously incorporated by reference herein.In one of these embodiments, such a delivery device uses a probe andneedle mechanism that automatically stops the advance of the device uponinsertion into a body cavity or space (e.g. abdominal cavity), whichminimizes user error and improves patient safety.

Under some of these embodiments, the probe of the delivery device ishollow and allows transmission of a synthetic polymer formulation withor without additional substances from a holding chamber or canister toflow through the device and hollow probe into the patient's anatomiccavity or space of interest. Under some embodiments, the polymer isinitially contained within a canister, from which it is dispensed viatubing and/or other mechanism. Canisters for delivering substances underpressure are well known in the art and different embodiments utilizedifferent types of expansion tanks, which under some embodiments containone or more of the following features: aerosol, screw-on, easy click on,pierceable. These deliver the polymer in a pre- and/or post-foaming gelconfiguration. Under several embodiments, these canisters contain one ormore propellent gases, as is well established in the art. Under severalembodiments, the propellent gas is kept separate from the polymer to bedelivered by a membrane and/or bag, so that it can transmit pressure butdoes not directly mix with the agent to be delivered to the body.

Under various embodiments, the synthetic polymer formulation expandsonce reaching the body cavity or space (e.g. abdominal cavity) to reduceand/or stop bleeding. Under some of these embodiments, the injectedmaterial does not need to chemically react inside the abdominal cavity,rather its innate properties and/or a propellant pushing the materialinto the cavity causes it to expand once reaching the desired space. Thepolymer formulation expands to partially or fully fill the cavity andprovide pressure, physical tamponade, and/or deliver bioactivesubstances to prevent, reduce, and/or stop bleeding.

Some of these embodiments include one or more valves (e.g. control,regulator, pressure, vent, relief, head pressure, dispensing, one-way,poppet), which automatically senses the appropriate pressure andterminate the insertion of the polymer formulation into the cavity atthe desired pressure. Examples include both single and double stageregulators. They can be an integral device with an output pressuresetting, a restrictor and a sensor all in the one body, or consist of aseparate pressure sensor, controller and flow valve. Under manyembodiments, there is also a main on-off valve (e.g. ball valve) thatmay be manually (e.g. turning of valve lever, pushing of electronicbutton) or automatically (e.g. connect to a countdown clock, tied to amore complex electronic algorithm) engaged. Under some embodiments, theinsertion of polymer formulation into the cavity terminates at a setvolume. Under some embodiments, the system controls pressure so as tomaximize hemostasis while minimizing injury from high pressure (e.g.abdominal compartment syndrome, intestinal injury, high peak lungpressure). Under various embodiments, the system allows controlledpressure to be delivered and/or maintained to a selected body area (e.g.body cavity) by the user (e.g. under manual and/or automated control).Under one example of an embodiment wherein pressure is under manualcontrol, the user utilizes an incorporated pressure gauge to determinehow much formulation and thus pressure to deliver. Under another exampleof an embodiment wherein pressure is under manual control, the useropens the main on-off valve of the system, which then deliversformulation to maintain a set pressure within a cavity being treatedwhile open. Under other embodiments, the system is set for a specificpressure profile and it automatically stops delivery at a peak pressureand/or adds additional polymer at lower pressures to deliver the desiredpressure profile.

For example, under some embodiments, the device delivers polymer to abody cavity to a peak pressure of 60 mmHg, at which time itautomatically stops additional polymer delivery. For the first 5 minutesof delivery, the device works to maintain a pressure between 50-60 mmHg(e.g. above the patient's mean arterial pressure), delivering morepolymer if the pressure falls below the lower cutoff (i.e. 50 mmHg) andstopping delivery if it reaches the maximum set (i.e. 60 mmHg). Undersome embodiments, the device then has other pressure settings for one ormore subsequent time periods (e.g. pressure set to 5-10 mmHg for thenext 60 minutes). Under some embodiments there is additionally a pathwaythrough a needle to remove gas and reduce the pressure if it is toohigh. The exact pressure and time duration settings vary under differentembodiments and thus this invention is not limited to specific pressuresor time periods as these can easily be changed by a person havingordinary skill in the art.

Under some embodiments, the present invention contains one or moreadditional substances to assist with preventing, slowing, and/orstopping bleeding. These include, but are not limited to, components ofthe intrinsic clotting pathway (e.g. factors XI, IX, VIII); componentsof the extrinsic clotting pathway (e.g. transmembrane receptor tissuefactor, plasma factor, factor VII/VIIa); tranexamic acid and other aminoacids and their analogs; epinephrine and other vasoconstrictors;thrombin; fibrinogen; potassium ferrate; cellulose, including oxidizedand/or regenerated cellulose; kaolin; smectite granules; zeolite;chitosan; sodium carboxymethylcellulose; amylopectin; microfibrillarcollagen; propyl gallate; aluminum sulfate; fully acetylatedpoly-N-acetyl glucosamine; related substances; and other clottingagents, platelet aggregators, and substances that reduce or stopbleeding.

Under some embodiments, the present invention contains one or moreadditional substances to assist with preventing, slowing, and/orstopping bacterial and/or other infections. These include, but are notlimited to, antimicrobial agents (e.g. antibiotics), disinfectants (e.g.alcohols, aldehydes, oxidizing agents, phenolics, quaternary ammoniumcompounds, silver-based products, copper-based produces, and/or otherdisinfectants), and/or other agents (e.g. antifungals). Under someembodiments, a synthetic polymer with one or more of these additionalsubstances is delivered into a body cavity. Under other embodiments, asynthetic polymer with one or more of these additional substances issprayed or otherwise delivered to an external wound or area.

Under some embodiments, the present invention contains one or more ofthe previously mentioned additional substances at normal concentrationsfor administration in the body. Under some embodiments, the presentinvention contains one or more of the previously mentioned additionalsubstances at concentrations higher than could be used via oral and/orparenteral administration because it is delivered directly to a cavityand/or space. Thus, the body cavity and/or space has a highconcentration of the additional substance, but there is a lowerconcentration systemically or away from that cavity and/or space. Thisallows a high concentration at the needed site but a lower concentrationaway from it, which minimizes systemic and/or more distal side effects.For example, a clotting agent could be used at very high concentrationwhen administered directly to the abdominal cavity, to cause clotting ofany traumatic bleeding vessels there, when administering such a highconcentration of the agent is not possible via oral and/or parenteralrout because it would cause systemic clotting of healthy vessels in thebody. Similarly, an antibiotic such as gentamicin could be deployed atvery high concentrations in the abdominal cavity, which if given viaparenteral route would have toxic effects.

Under various embodiments, the present invention has one or more of thefollowing characteristics: it is field-adapted with a small size, easilyfitting into a medical field kit; it has a delivery device for safe andrapid deployment by medics or other non-surgeon providers; it is stablewithout need for refrigeration, with the ability to maintain activityunder the environmental extremes experienced in military operations; itis rapidly applied to penetrate deep into intra-abdominal injuries ofall shapes and sizes; it induces hemostasis; it provides a deliverymechanism for a wide range of additional bioactive clotting agents; itprevents bacterial adhesion and/or biofilm formation; it inhibitsdrug-resistance mechanisms in multidrug-resistant strains of bacteria;it is partially or fully resorbable by the body; it has a low risk ofcomplications; it is not exothermic and/or has minimal risk ofiatrogenic thermal injury to organs; it is transparent does not discolorthe abdominal organs; it is water soluble; it may be quickly and easilywashed away for easy removal if needed for emergent laparotomy surgery;it contains no toxic substances or materials with potential for adverseenvironmental effects; it uses expanding and/or propellant componentsthat are non-ozone depleting; and/or it is made in whole or part fromsynthetic, inert polymers that are already FDA and EU-approved forpharmaceutical applications.

Under several embodiments, the synthetic polymer formulation comprises asolution of one or more copolymers of ethylene oxide (EO) and propyleneoxide (PO) (e.g. in an aqueous solution), in combination with one ormore volatile or gaseous expanding and/or propelling components which isdissolved in, or evenly dispersed throughout, said copolymer solution.Such copolymers may be a random or block copolymer of EO and PO havingan average molecular mass of about 1 kg/mol to about 100 kg/mol, and amass ratio of EO to PO of between 5:95 to 95:5. In some of theseembodiments, the block copolymer is a poloxamer. Poloxamers are linearA-B-A triblock copolymers of EO and PO having the general formula(EO)_(x)(PO)_(y)(EO)_(x), where x and y represent the number of EO andPO monomer units in the block. Different poloxamers having a molecularmass in the range of about 1 kg/mol to about 15 kg/mol and EO:PO ratiosby mass of between 8:2 and 1:9 are commercially available, (e.g.,PLURONIC® copolymers from BASF). In certain advantageous embodiments,the block copolymer is a poloxamer produced in NF grade for medicalapplications, and which is approved for pharmaceutical use. Examplesinclude poloxamers P188, P237, P338 and P407, also known as Pluronic®F68, F87, F108 and F127; the ranges of molecular mass and mass % of EO(as oxyethylene) for each of these poloxamers is shown in FIG. 15.

Under several embodiments, the one or more volatile expanding and/orpropelling components is a compressed gas or volatile liquid that isdissolved within or evenly dispersed throughout the polymer solutionunder elevated pressure. The compressed gas or volatile liquid expandsand/or evaporates into a gaseous form due to the decrease in pressure asit is released from its storage container, thereby causing the polymersolution to foam (e.g. within the body cavity). This gas or volatileliquid may be any one of the many medical grade gases suitable to bedelivered to the body. Under several embodiments, this gas or volatileliquid is one or more organohalide compound, such as a fluorinatedhydrocarbon (i.e. hydrofluorocarbon, or HFC) or a perfluorocarbon. Forexample, under some embodiments, the synthetic polymer formulation ismixed with 1,1,1,2-tetrafluoroethane (i.e. norflurane, R-134a) in liquidform under a pressure of 100 pounds per square inch (psi). This mixtureof polymer and hydrofluorocarbon provides a foaming polymer solutiononce discharged from the storage canister. Thus, under multipleembodiments, no chemical reaction with any components within the body(e.g. water) is required to cause the synthetic polymer formulation tofoam.

Under several embodiments, the synthetic polymer formulation is anaqueous solution of a block copolymer (e.g. a poloxamer) of a suitabletype and in an adequate concentration to exhibit reverse phase changeproperties, such that the solution increases markedly in viscosity (e.g.forming a strong gel when it is warmed) and decreases in viscosity whenit is cooled. By selecting the type of block copolymer and anappropriate concentration in solution, this reverse phase change can betailored to occur over a desired temperature range such that thesolution is a low viscosity liquid at temperatures below thatanticipated to occur in the body, for example less than about 5-10 □Cbut is a highly viscous gel at temperatures above about 20-30 □C.

Under many embodiments, the reverse phase properties of such a blockcopolymer solution provide a key advantage of the current invention,such that after delivery to the body (e.g. into the an internal cavity,sprayed externally) that the synthetic polymer formulation is as viscousas possible and have the form of a highly viscous gel in order to exertthe maximum hemostatic effect by physical tamponade (i.e., by providinga physical barrier to resist the flow of blood from damaged bloodvessels). However, in practice (e.g. use in acute abdominal hemorrhage)it is also necessary to deliver the solution to the patient rapidly tostop the bleeding as soon as possible and ideally through a smalldiameter tube or needle, which would be difficult or impossible toachieve if the solution were a highly viscous gel during delivery. Theuse of a synthetic polymer formulation with appropriately tailoredreverse phase properties in conjunction with a suitable choice ofexpanding gas provides a simple solution to these conflictingrequirements. In many embodiments, the reverse phase characteristics ofthe polymer solution and the properties of the expanding gas arearranged such that the cooling effect due to expansion of the gas as thesolution is discharged ensures that the polymer solution is in lowviscosity liquid form as it exits the storage container, therebyfacilitating rapid delivery to the patient. After it is delivered, thebody temperature of the patient causes the polymer solution to increasein viscosity, forming a highly viscous gel foam, which provides a muchstronger tamponing effect than could be achieved if the polymer solutionremained in the liquid form. An additional advantage of the reversephase properties of the polymer solution is that the viscous gel canlater be easily removed, if necessary, by cooling (e.g. by irrigationwith cool water or normal saline within the abdominal cavity) whereuponit reverts to liquid form.

From the foregoing, it can be seen that the present invention providessystems and methods relating to synthetic polymer formulations withinanimals, especially humans. Moreover, it should also be apparent thatthe device can be made in varying lengths, sizes and capacities, and theprecise composition of the synthetic polymer formulation, the amountdelivered and the rate and pressure at which it is delivered may bevaried appropriately to treat adults, children, and infants. While theinvention has been described with a certain degree of particularity, itis manifest that many changes may be made in the details of constructionand the arrangement of components without departing from the spirit andscope of this disclosure. It is understood that the invention is notlimited to the embodiments set forth herein for purposes ofexemplification and that elements of certain embodiments can be combinedwith elements of other embodiments. Additional objects, advantages, andnovel features of the invention will be set forth in the descriptionwhich follows, and will become apparent to those skilled in the art uponexamination of the following detailed description and figures. It shouldbe understood that not all of the features described need beincorporated into a given system or method.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a perspective view of part of a system to deliver syntheticpolymer formulations to the body in accordance with one embodiment, asassembled prior to use.

FIG. 2 is a cross section view of part of a system to deliver syntheticpolymer formulations to the body in accordance with one embodiment, asassembled prior to use.

FIG. 3 is a cross section view of part of a system to deliver syntheticpolymer formulations to the body in accordance with one embodiment, asassembled prior to use.

FIG. 4 is a cross section view of part of a system to deliver syntheticpolymer formulations to the body in accordance with one embodiment, asassembled prior to use.

FIG. 5 is a cross section view of part of a system to deliver syntheticpolymer formulations to the body in accordance with one embodiment, asassembled prior to use.

FIG. 6 is a cross section view of part of a system to prepare and todeliver synthetic polymer formulations to the body in accordance withone embodiment, as assembled prior to use.

FIG. 7 is a diagrammatic representation of the foam testing apparatusused to evaluate synthetic polymer formulations to the body inaccordance with certain embodiments.

FIG. 8 is a comparison of foaming polymer formulations containingPluronic F68 in aqueous solution (37.5%, 41%, and 45% w/w) blended with10% w/w 1,1,1,2-tetrafluoroethane (TFE).

FIG. 9 is a comparison of foaming polymer formulations containingPluronic F68 in aqueous solution (37.5% w/w) blended with 5% and 10% w/wTFE.

FIG. 10 is a comparison of foaming polymer formulations containingPluronic F127 in aqueous solution (25%, 30%, and 37.5% w/w) blended with5% w/w TFE.

FIG. 11 is a comparison of foaming polymer formulations containingPluronic F127 in aqueous solution (30% w/w) blended with 5% and 10% w/wTFE.

FIG. 12 is a comparison of foaming polymer formulations containingPluronic F108 in aqueous solution (37.5% w/w) blended with 2.5%, 5%, and10% w/w TFE.

FIG. 13 is a Comparison of Pluronic F68, F108, and F127 foaming polymerformulations.

FIG. 14 is a graph of porcine survival over 60 minutes after injury withintraperitoneal deployment of Pluronic F68 foam held at a pressure of 60mmHg for at least 5 minutes.

FIG. 15 is a table showing ranges of molecular mass and mass % of EO (asoxyethylene) for NF grades of poloxamers P188, P237, P338, and P407, perUSP-NF 23.

FIG. 16 is a table showing comparison of foam expansion, stability, andvolume.

FIG. 17 is a table showing gelation temperature for aqueous Pluronicsolutions.

DETAILED DESCRIPTION OF THE INVENTION

Referring to the drawings, FIGS. 1 and 2 illustrate one embodiment ofpart of the present invention. For ease of reference, distal shall referto the end of the device farthest away from the user, while proximalshall refer to the end of the device closest to the user.

Under this embodiment, stabilizer 30 initially extends distally fromholder 40 along the tract of needle 20, to provide a mechanism forautomatically halting the forward movement of needle tip 22 and probetip 52 upon penetration into a body cavity (e.g. peritoneal cavity).Holder 40 has one or more phalanges 49 that are resiliently biasedmedially, but when pushed laterally by probe holder 60 are caused tointeract with grooves 34 on rods 32 so as to halt the movement ofstabilizer 30 in respect to holder 40.

Biased by spring 80, in its distal position probe holder 60 extends tip52 of probe 50 out distally from tip 22 of needle 20. Additionally, thispushes phalange(s) 49 laterally to reversibly lock with grooves 34 andinhibit the movement of rod(s) 32 and thus stabilizer 30 in relation tothe rest of device 10.

When needle 20 pierces the skin and enters into a cavity (e.g.peritoneal cavity), probe tip 52 to moves proximally in reference toneedle tip 22. This causes holder 60 on probe 50 to also move proximallyin reference to housing 40. This in turn allows phalanges 49, which arebiased medially, to move medially and thus unlock from groove(s) 34 toallow rod 32 and thus stabilizer 30 to move in relation to housing 40.Thus, when a general distal biasing of the device is provided by theuser, stabilizer 30 remains flush with skin of the body while the restof the device moves distally, thus inserting needle 20 further into thecavity.

Once probe tip 52 and needle tip 22 have reached a body cavity, spring80 is free to move probe tip 52 distally in reference to needle tip 22,which allows holder 60 to move distally in reference to housing 40 andthus forces phalange(s) 49 laterally to again lock with grooves 34 andinhibit the movement of rod(s) 32 and thus stabilizer 30 in relation tohousing 40. This, in turn, prevents needle tip 22 from moving furtherinto the cavity, thus minimizing the chances of injuring vitalstructures. Under one embodiment, there is an airtight seal betweenprobe 50 and housing hole 42, which may include the use of an O-ringand/or other sealing mechanisms.

When probe tip 52 has entered the cavity, there is then a contiguouspathway between connection port 90 with luer lock groove 48 through thedevice and into probe tip 52. Reversibly or irreversibly connected toconnection port 90, in some embodiments via standard luer lock, is astandard, high-pressure, tapered, or otherwise configured tube (notshown) from a delivery container, such as one shown in FIG. 3, 4, or 5and described below. Thus, when deployment is initiated, polymerformulation (e.g. as a partial or complete liquid, or as foam) isdispensed from the delivery container, travels through the connectiontubing, and proceeds through the continuous pathway within the portionof the device shown in FIGS. 1 and 2 to be dispensed into the bodycavity of interest.

FIG. 3 illustrates a delivery container suitable for holding anddelivery of the synthetic polymer formulation under one embodiment. Thebody of the delivery container consists of a pressurizable vessel 102with a closure 112 containing a suitable release valve mechanism 114.The vessel, closure, and release valve can withstand an internalpressure (e.g. up to 200 pounds per square inch). Internally, the vesselis divided into an upper space 110, and a lower space 104, by afreely-moving piston 108. The piston 108 bears a pressure-tight seal 106that prevents movement of liquid or gas from one space into the other.The seal 106 may be integral to the piston or may be created using aseparate sealing component such as an O-ring. The release valvemechanism opens into an exit nozzle 116 which has an appropriate means(illustrated in FIG. 3 as a male threaded connector 118 as an example)to attach the delivery container to a suitable delivery device (e.g. thedevice illustrated in FIGS. 1 and 2 via the aforementioned tubing anddescribed above). The vessel also contains a gas-tight valve 120 orother similar means to allow a gas or volatile liquid to be introducedinto the lower space 104. When the delivery container is fully assembledand ready for use, the upper space 110 contains the synthetic polymerformulation optionally mixed with a first compressed gas or volatileliquid (the “expanding gas”) which causes the synthetic polymerformulation to foam when released from the delivery container. The lowerspace 104 contains a second gas or other highly volatile liquid (the“driving gas”). The driving gas may be either be introduced into thelower space of the delivery container prior to use (e.g. at the time thecontainer is initially filled with the synthetic polymer formulation) orit may be introduced into the lower space of the delivery container atthe time of use (e.g. by connection to an external source such ascompressed air supply or a pressurized gas cylinder).

A key feature of this embodiment is that the driving gas in the lowerspace 104 is physically separated from the synthetic polymer formulationin the upper space 110. An advantage of this embodiment is that thepressure of the driving gas in the lower space 104 can be arranged toalways exceed the pressure of the expanding gas in the upper space 110until the contents of upper space 110 have been sufficiently dischargedfrom the container, thereby maintaining the expanding gas in acompressed form until the synthetic polymer formulation has beenreleased via the valve mechanism 114 into the exit nozzle 116.

FIG. 4 illustrates a delivery container suitable for holding anddelivery of the synthetic polymer formulation under another embodiment.The body of the delivery container consists of a pressurizable vessel130 with a closure 132 containing a suitable release valve mechanism 140and rated for an internal pressure (e.g. up to 200 pounds per squareinch). A flexible, gas impermeable bag 134 is attached with a gas-tightseal 136 to the closure 132, thereby separating the inside of the vesselinto two separate spaces. One of said spaces is the interior of the bag134; this “internal space” communicates with the exit nozzle 142 via therelease valve mechanism 140. The other space, “external space” 138, isthe actual or potential space between the outside of the bag 134 and theinside wall of the vessel 130. The release valve mechanism 140 opensinto an exit nozzle 142 with an appropriate means (illustrated in FIG. 4as a male threaded connector 144 as an example) which allows thedelivery container to be attached to a suitable delivery device such asdescribed above. The vessel also contains a gas-tight valve or 146 orother similar means, such as a gas-tight elastomeric septum, to allow agas or volatile liquid to be introduced into the external space 138.When the delivery container is fully assembled and ready for use, thebag 134 contains the synthetic polymer formulation optionally mixed withan expanding gas which causes the synthetic polymer formulation to foamwhen released from the delivery container. The external space 138contains a second gas or other highly volatile liquid (the “drivinggas”). The driving gas may be introduced into the external space of thedelivery container 138 via the valve or septum or other means 146 eitherprior to use, (e.g. at the time the container is initially filled withthe synthetic polymer formulation) or alternatively at the time of use(e.g. by connection to an external source such as compressed air supplyor a pressurized gas cylinder). This embodiment shares a key feature tothat shown in FIG. 3, namely that the synthetic polymer formulationexpanding gas is physically separated from the driving gas, such thatthe pressure of the driving gas outside of the bag can be arranged toalways exceed the pressure of the expanding gas in the upper space untilthe contents of the discharged from the container, thereby maintainingthe expanding gas in a compressed form until the synthetic polymerformulation has been released via the valve mechanism 140 into the exitnozzle 142.

FIG. 5 illustrates a container suitable for holding and delivery of thesynthetic polymer formulation under another embodiment. The body of thedelivery container consists of a vessel 160 with a closure 162containing a suitable release valve mechanism 170 and can hold aninternal pressure (e.g. up to 200 pounds per square inch). The releasevalve mechanism opens into an exit nozzle 172 with an appropriate means(illustrated in FIG. 5 as a male threaded connector 174 as an example)which allows the delivery container to be attached to a suitabledelivery device such as described above. A “dip-tube” 164 is attachedvia a gas-tight connection 166 to the closure 162 and extends towardsthe bottom of the vessel. The dip tube is designed to ensure that thelower end 168 always remains open during use, by using a tube slightlyshorter than the internal height of the vessel below the closure, or bymaking a cut-out in or near to the end of the tube. When the deliverycontainer is fully assembled and ready for use, the vessel contains thesynthetic polymer formulation mixed with a compressed gas or volatileliquid. In this embodiment, when the release valve is opened, thecompressed gas or volatile liquid initially expands or evaporates toexpel the synthetic polymer solution from the container, andsubsequently also causes the synthetic polymer solution to foam once ithas been released via the valve mechanism 170 and enters the exit nozzle172. Unlike the embodiments described in relation to FIGS. 3 and 4, thisembodiment does not employ a physically separate expanding gas anddriving gas. Instead a compressed gas or volatile liquid eithercontained within or in contact with the synthetic polymer formulationpropels the formulation out of the delivery container. In somevariations of this embodiment, the compressed gas or volatile liquidcauses the synthetic polymer formulation to foam after it has beendispensed from the container.

Under some embodiments, the synthetic polymer formulation is deliveredby opening the releasing valve by pushing a button, pulling a tab, orother manually-activated releasing mechanism. Under other embodiments,the delivery of the synthetic polymer formulation may be controlledautomatically or semi-automatically by sensing when the probe hasentered the cavity space, or in response to absolute pressure or changesin pressure within the cavity (e.g. by a sensor mechanism within thecavity itself or connected to the dispersal path earlier within thesystem). Such control mechanisms may be used to initiate the delivery ofthe polymer formulation, to override user-activated delivery under somecircumstances (e.g. stopping delivery after a certain amount of time),and/or to control the polymer formulation flow rate or the maximum orminimum pressure developed within the body cavity (e.g. through aregulator mechanism). Such control mechanisms may also allow foradjustment of the pressure developed within the body cavity byadministering additional polymer formulation or by venting any excess,either manually or in an automated manner under feedback control.

Some of these embodiments include one or more valves (e.g. control,regulator, pressure, vent, relief, head pressure, dispensing, one-way,poppet), which automatically sense the appropriate pressure andterminate the insertion of the polymer formulation into the cavity atthe desired pressure. Examples include both single and double stageregulators. They can be an integral device with an output pressuresetting, a restrictor and a sensor all in the one body, or consist of aseparate pressure sensor, controller and flow valve. Under manyembodiments, there is also a main on-off valve (e.g. ball valve) thatmay be manually (e.g. turning of valve lever, pushing of electronicbutton) or automatically (e.g. connect to a countdown clock, tied to amore complex electronic algorithm) engaged.

Under some embodiments, the delivery container is partially orcompletely integrated into the delivery device, to minimize parts.

EXAMPLES

The following examples more particularly describe certain embodiments ofthe invention but are intended for illustrative purposes only, sincemodifications and variations will be apparent to those skilled in theart.

For a series of experiments to study the physical properties of thefoaming synthetic polymer formulation (Examples 1 and 2 below), adelivery container (FIG. 6) was constructed having clear walls to enabledirect visualization of the polymer formulation. The delivery containershown in FIG. 6 has the same design and components as illustrated anddescribed in FIG. 3, with the addition of a stirring paddle 122 withinthe upper space attached to a rotating shaft 126, which communicateswith the exterior of the container via a pressure-tight rotary seal 124.This arrangement allows the synthetic polymer formulation and thecompressed gas or volatile liquid (the expanding gas) to be added to thecontainer sequentially and then mechanically stirred and mixed togetherwithin the container by rotating the shaft 126.

Example 1: Preparation of Foaming Poloxamer Formulations

Aqueous solutions of poloxamers P188, P338, and P407 (Pluronic® F68,F108, and F127 respectively) at concentrations from 25% w/w to 45% w/wwere blended with from 2.5% to 10% by weight of1,1,1,2-tetrafluoroethane (aka Norflurane, HFC-134a) in liquid formunder pressure using a delivery container with the design illustrated inFIG. 6 and described above. The general method for preparation of everyformulation was as follows:

Preparation of Poloxamer Solutions:

Reverse osmosis purified water was chilled in a laboratory refrigeratorto approximately 4° C. before use. The required mass of chilled waterwas first weighed into a suitable laboratory pail and the calculatedamount of poloxamer was then slowly added to the pail under constantmixing using a high-shear mechanical stirrer. After all the poloxamerhad been added, a lid was placed onto the pail and it was transferred toa refrigerator. Periodically, the pail was removed from the refrigeratorand the contents were re-mixed using the mechanical stirrer, after whichit was returned to the refrigerator. The process was repeated until thepoloxamer was completely dissolved, which required up to 2 days for thehighest concentration solutions.

Filling of Delivery Container:

Poloxamer Solution:

Both delivery container valves 114 (upper valve) and 120 (lower valve)were opened and positive air pressure was applied to the upper valve tocause the piston to move to the bottom of the container. The deliverycontainer was placed on a balance and tared. Approximately 450 mL of thecold poloxamer solution (at approximately 4° C.) was then added to theupper space 110 of the delivery container through the upper valve, andthe total mass of the added solution was recorded. A positive airpressure was then applied via the lower valve to move the piston upwardssufficiently to expel any remaining air from the upper space, afterwhich both valves were closed.

1,1,1,2-tetrafluoroethane

A pressurized cylinder of 1,1,1,2-tetrafluoroethane (TFE) was attachedto the exit nozzle 116 via a length of flexible high-pressure tubing,and the delivery container was replaced on the balance and tared again.The upper valve of the delivery container was then opened, and liquid1,1,1,2-tetrafluoroethane was dispensed slowly from the pressurizedcylinder until the desired mass of TFE had been transferred into thedelivery container. The upper valve was then closed, and the deliverycontainer was pressurized to 100 psi with air via the lower valve toensure that all the added TFA, which has a vapor pressure of 71 psi at20 □C, was compressed back into liquid form.

Mixing of Poloxamer Solution and TFE:

After both the cold poloxamer solution and the TFE were added, they weremixed together under pressure using the stirring paddle 122 attached toan electric drill. During mixing, care was taken to ensure thetemperature always remained below the gelation temperature for thespecies of poloxamer being used and its concentration in solution (FIG.17). The two components, both initially clear liquids, rapidly blendedtogether to form a macroscopically homogeneous emulsion that has a muchhigher viscosity than either individual component. (Note that thecontents remained below the gelation temperature of the poloxamersolution throughout the mixing process). Mixing appeared to be completewithin 2-3 minutes; no further change was noticeable with prolongedstirring. As far as could be observed though the clear walls of thecontainer the mixture showed no tendency to phase separate for up to 3months of refrigerated storage. Since TFE is poorly soluble in water,the ease of mixing, and the homogeneity and stability of the resultingblend were unexpected and were presumably due to the amphiphilicproperties of the poloxamer. The results of the blending process werequalitatively the same for each of the poloxamers evaluated, regardlessof the poloxamer concentration, and for all proportions of TFA from 2.5%to 10% w/w.

Example 2: In Vitro Evaluation of Foaming Poloxamer Formulations

Foam Height Testing:

The volume and stability of the foam produced by each foaming polymerformulation was assessed using a simple foam height testing apparatus asshown in FIGS. 7A, 7B, and 7C. The apparatus (FIG. 7A) consists of avertically mounted 120 cm high and 6.06 cm internal diameter clearpolycarbonate tube 200. The lower end of the tube is sealed except for a1 cm diameter input port 202 through which the foam is introduced. Thetube contains a piston of negligible mass 204 which seals the tube, butwhich can move freely up and down. A column of water 206 is layeredabove the piston, the height of which provides a reproducible and easilymeasured pressure against the expansion of the foam.

In use, the delivery container was attached via a flexible tube to theport 202 and the foaming polymer formulation was introduced into thetesting apparatus after which the input port was closed (FIG. 7B). Theexpanding column of foam caused the piston to rise until it reached amaximum height, at which time (t=0) the piston height 212 and height ofthe foam column 214 was recorded. The precise mass of foaming polymerformulation added to each tube was measured by weighing the deliverycontainer before and after the polymer formulation was dispensed. Afterthe initial expansion, the foam column slowly collapsed leaving justexpanding gas in the upper region of the tube as shown in FIG. 7C. Theheight of the foam column 214 and the piston height 212 was measured atregular intervals for up to four hours after t=0. To normalize the datafor the precise amount of polymer formulation that was dispensed foreach experiment, two values were calculated for each time point; theFoam Ratio, which is the height of foam column divided by the totalpiston displacement (i.e., the height of the foam column plus the heightof the gas-filled space above the foam), and the Specific Volume, whichis the volume of the foam column (i.e., the height of the foam column xthe cross-sectional area of the tube) divided by the total mass of thepolymer formulation added to the tube.

Test Design:

The principal goal of the experiments presented herein was to evaluatethe potential utility of the foaming polymer formulations to controlnoncompressible hemorrhage within a specific body cavity (i.e.noncompressible intra-abdominal hemorrhage within the peritonealcavity). Therefore, the height of the water column (and hence thepressure resisting the expansion of the foam) was set at approximately13.5 cm to simulate the upper limit of normal intra-abdominal pressure(i.e. approximately 10 mmHg). For all studies TFA was used as theexpanding gas. Each polymer formulation was evaluated in triplicate.

Presentation of Data:

Example results from the foam height testing are shown in graphical formin FIGS. 8-13 and are summarized numerically in FIG. 16.

In each Figure, the upper graph shows the Foam Ratio (FR) over time fora two-hour period. Each foaming polymer solution rapidly expanded afterit was dispensed into the tube, reaching a maximum foam height within0-2 minutes, after which the foam height gradually declined over time.For a numerical comparison, the maximum Foam Ratio (FR_(Peak)) and theFoam Ratio after 60 minutes (FR₆₀) were recorded; these data are shownin FIG. 16. Since the Foam Ratio represents the proportion of theexpanding gas within the foam at any time point, FR_(Peak) shows theproportion of gas that is initially incorporated into the foam, whileFR₆₀ is a measure of the collapse of the foam over time. The percentageratio of FR₆₀ to FR_(Peak) relates the height of the foam after 60minutes compared to the peak foam height and is therefore an indicatorof foam stability (Foam Stability Index, FSI).

The lower panel of each Figure shows the Specific Volume (SV) of thefoam over the two-hour observation period. SV is a measure of the totalvolume of the foam normalized for the mass of the formulation that wasdispensed and is therefore a function of both the overall volume of theexpanding gas and the proportion of the expanding gas that is containedwithin the foam at any given time. For highly stable foams, the SV willincrease slightly over time as the system reaches equilibriumtemperature and the total gas volume continues to slowly expand. Incontrast, for poorly-stable foams the SV decreases over time because therate of collapse exceeds any increase in volume due to thermal effects.(Note that the FR is a ratio of the total foam volume to the total gasvolume and therefore is not affected in the same way by changes intemperature). For a numerical comparison, the maximum Specific Volume(SV_(Peak)) and Specific Volume after 60 minutes (SV₆₀) are shown inFIG. 16.

Results:

FIG. 8 shows the results for Pluronic F68 solutions at three differentconcentrations, 37.5%, 41%, and 45% w/w. After dispensing, eachformulation rapidly filled the tube with a fine-textured foam containingsmall evenly-sized bubbles. The FR_(Peak) values (FIG. 16) ranged from0.94 to 0.96, indicating that 94% to 96% of the expanding gas wasinitially entrapped within the foam. For all three concentrations ofPluronic F68, the foams were stable and subsided only very slowly overthe two-hour observation period, as evidenced by FR₆₀ values from 0.89to 0.92, and a corresponding Foam Stability Index (FSI) of 92%-98%. TheSV values were also similar for all three concentrations tested, rangingfrom 21 to 25.5 cm³/gram.

The effects of using a different proportion of TFE to expand the foam isillustrated in FIG. 9. For these experiments a 37.5 w/w Pluronic F68solution was blended with either 5% or 10% by weight of TFE. With eitheramount of TFE, the initial FR and the change in FR over time were almostidentical (upper panel) indicating that a similar proportion of thetotal gas volume was entrapped within the foam. The SV for the 10% TFEformulation, however, was approximately double that of the 5% TFEformulation.

As shown in FIGS. 10 and 11, the results obtained using Pluronic F127were quantitatively and qualitatively different from those obtained forPluronic F68. FIG. 10 shows the results for Pluronic F127 solutions atfour different concentrations, 25%, 30%, 34%, and 37.5% w/w blended with5% by weight TFE. The lowest (25%) and highest (37.5%) concentrationsproduced foams that only partially filled the tube when first dispensed;for these concentrations the FR_(Peak) values of 0.57 and 0.44 indicatethat a large proportion of the TFE was not incorporated into the foam asit formed. The two intermediate concentrations, 30% and 34%, produced afoam that initially filled most of the tube (FR_(Peak) of 0.90-0.91) butwhich quickly collapsed. For all concentrations, the FR fell to about0.4 within about 20 minutes. The Foam Stability Index for the 30% and34% w/w Pluronic F127 formulations was 26% and 38% respectively, muchlower than was observed for the Pluronic F68 formulations. The FSI wasnot calculated for the two formulations which failed to expand properlyinitially. The SV values observed for the Pluronic F127 solutions wereconsistent with the limited expansion and reduced stability of the foamas shown by the FR data, and do not provide significant furtherinformation.

The effects of using a different proportion of TFE to expand thePluronic F127 foam is illustrated in FIG. 11. For these experiments a30% w/w Pluronic F127 solution was blended with either 5% or 10% byweight of TFE. In marked contrast to the results for Pluronic F68 (FIG.9), the formulation containing 10% TFE did not expand fully, reaching aFR_(Peak) of only 0.54 compared to 0.91 for the 5% TFE formulation. Thisresult suggests that the volume of gas present exceeded the maximumamount that could be retained in the foam as it formed. This idea issupported by the SV data: the SV_(Peak) for the 10% TFE formulation was11.4 cm³/g compared to 9.2 cm³/g for the 5% TFE formulation, indicatingthat only about 20% of the additional TFE had been incorporated into thefoam.

Visual inspection of the foams was consistent with the experimentalfindings: the Pluronic F68 formulations produced homogeneous-lookingfoams with small uniform bubbles, whereas those produced using PluronicF127 at all concentrations had a more heterogeneous structure, withsignificant variability in the size of the bubbles and occasional voids.

FIG. 12 shows the data for Pluronic F108 at 37.5% w/w with differentproportions of TFE in the blend—2.5%, 5%, and 10%. Each formulationinitially produced a (visually) good-quality foam which expanded to fillmost of the tube. FR_(Peak) ranged from 0.86 to 0.92. The foams remainedstable for about 15 minutes. By 20 minutes the 10% TFE foam collapsedquickly, reaching a FR of about 0.12 by 40 minutes. In contrast the 2.5%and 5% TFE foams subsided relatively slowly. The difference in stabilityis captured in the FSI values. The SV graphs show that each formulationinitially expanded to approximately the expected volume based upon theTFE content: SV_(Peak) was 4.2, 11.1, and 20.6 cm³/g for the 2.5%, 5%,and 10% TFE formulations respectively.

Selected results for the three different Pluronics are compared in FIG.13. Pluronic F68 formulations consistently produced a uniform and stablefoam which captured and retained most of the expanding gas withoutsignificant collapse for at least two hours; these results were observedover a range of Pluronic F68 concentrations and a 2-fold difference inTFE content. Pluronic F108 formulations behaved in a similar manner toPluronic F68, but with one notable difference: although the foamproduced using 10% TFE as the expanding gas initially reachedapproximately the same SV, it collapsed more quickly for F108 than F68(30 minutes vs. >2 hours). Foams produced using Pluronic F127 alsocollapsed within 30 minutes; these foams also had a lower peak SV thanwas achieved with F68 or F108.

Overall it was found that aqueous solutions of each type of Pluronictested will produce a foam when blended with TFE, but the foamsexhibited different characteristics in terms of volume and rate ofcollapse. The results suggest that the foam properties could be tailoredto a specific application, for example if a foam with a longer orshorter lifetime were desired, by selecting the most suitable Pluronictype.

Example 3: In Vivo Evaluation of Foaming Poloxamer Formulation forHemostasis

Based upon the findings in the foregoing examples, a foaming PluronicF68-based formulation was selected for evaluation as a potentialinterventional treatment in a porcine model of acute traumaticnon-compressible abdominal hemorrhage.

These following studies were performed using the laparoscopic swinemodel of non-compressible torso hemorrhage (NCTH) developed by Dr JamesRoss, as described in “A Laparoscopic Swine Model of Non-CompressibleTorso Hemorrhage” James D. Ross Ph D, et al. J Trauma Acute Care Surg,Volume 77, Number 3, Supplement 2, which is hereby incorporated byreference. The laparoscopic approach maintains both the integrity of theperitoneum and the natural tamponade effect of an intact abdominal wallwhile preserving the intrinsic physiologic responses to hemorrhage andtherefore provides a model of NCTH that reflects clinically relevantphysiology in trauma and uncontrolled hemorrhage. For splenectomizedanimals without intervention, the mortality rate in this model was 67%.

Preparation of Foaming Pluronic F68 Formulation: Since a larger volumewas required for the in vivo studies, a larger delivery container wasused that was functionally equivalent to that shown in FIG. 3. Thedelivery container was filled with a 45% w/w aqueous Pluronic F68solution, followed by 10% w/w of TFE, essentially as described inExample 1. However, mechanical stirring was not used to mix the PluronicF68 solution with the TFE. Instead, after the TFE was added to thecontainer, the pressure in the lower space was reduced to below thevapor pressure of the TFE to create a headspace, and the contents werethen mixed by manually shaking the container. After approximately oneminute of shaking, the contents increased in viscosity indicating thatthe components had combined together. Since the delivery containers usedfor these studies did not have clear walls, the contents could not beobserved directly. Therefore, in preliminary tests to evaluate theeffectiveness of the mixing technique, containers were discharged fully,and the flow rate and appearance of the foam were observed.Surprisingly, it was found that the brief period of manual shaking wasadequate to thoroughly mix the two components: throughout the entiredischarge period, the appearance of the foam remained identical tovisual inspection, including the consistency of bubble size. There wasno hesitation in the flow rate or voids in the foam stream to suggestthat any TFE remained in unmixed form. This was a very surprisingresult, which indicated that the two components had remarkable andunexpected miscibility. The fact that such thorough mixing could beachieved without the need for significant mechanical work suggests thatthe energy state of the blend may be lower than the individualcomponents and therefore that the blend would be likely to exhibitlong-term stability.

Experimental Design:

The foaming Pluronic F68 formulation was evaluated in six anesthetizedadult male Yorkshire swine. All animals were splenectomized prior to thestudy, and a pressure sensor was placed laparoscopically into theabdomen to allow monitoring the intra-abdominal pressure (IAP). At thestart of the experiment (T=0) a Grade V liver injury was created in eachanimal by laparoscopically transecting a lobe of the liver. To simulatea typical “pre-hospital” care scenario, the injured liver was allowed tobleed for 10 minutes prior to intervention. At T=10, the foamingPluronic F68 formulation was delivered to the abdominal cavity via alaparoscopic trocar until the IAP reached 60 mmHg, which was achieved inapproximately 1-2 minutes. The delivery was then halted, and thepressure was monitored. Additional foaming Pluronic F68 formulation wasdelivered as necessary to maintain the IAP approximately 60 mmHg for aminimum of 5 minutes. To avoid ischemic damage to the abdominal organs,the IAP was then allowed to naturally collapse over time. The experimentwas terminated one hour after injury (T=60) after which the animals wereeuthanized, and necropsy performed.

Results:

FIG. 14 compares the survival of the group of six animals that receivedthe foaming Pluronic F68 formulation against a historic group of twelveanimals that received no intervention. Five of the six animals in theintervention group (83%) survived for 60 minutes after injury comparedto six of twelve (50%) in the historic control group. The one animal inthe intervention group that did not survive had noticeably poor vitalsigns at T=10, prior to intervention. The results suggest the foamingPluronic F68 formulation prolonged survival in the intervention group,although the number of animals did not allow for a statisticalcomparison.

At necropsy, the foaming Pluronic F68 formulation was found to haveformed a thick viscous translucent gel in contact with theintra-abdominal organs. The gel did not interfere with the visibilityof, or access to, the damaged organ and was easily removed by hand or byirrigation with cold liquid.

CONCLUSIONS

Non-foaming reverse phase Pluronic solutions have been successfullyemployed and commercialized for control or prevention of bleeding fromsmall blood vessels during surgical procedures, and their wider use hasalso been proposed for the emergency management of other types ofhemorrhage, such as bleeding from deep wounds or within a body cavity,which can be difficult to control by other means such as directcompression. However, all reverse phase solutions have certain inherentcharacteristics which have hitherto limited their suitability foremergency use and/or for control of severe hemorrhage:

-   -   1. It is necessary for the solution to be in the liquid phase        prior to delivery to the patient. Consequently, it is necessary        to either store the Pluronic solution at a low temperature        (i.e., below its gelation temperature) until it is required, or        alternatively to provide an external means to cool the solution        immediately before use. The need for the solution to be either        refrigerated or cooled by some other means before use is        particularly undesirable for emergency treatment of hemorrhage        in the pre-hospital environment.    -   2. Control of bleeding from small blood vessels requires only a        relatively small volume of reverse phase Pluronic solution (e.g.        less than 1 mL). However, a much larger volume is required for        control of hemorrhage from a large wound or within a body        cavity. To attempt to control intra-abdominal hemorrhage using a        simple non-foaming Pluronic solution, it would be necessary to        introduce several liters of chilled liquid abdomen. The        solution, which consists predominantly of water, has a very high        specific heat capacity. Therefore, a significant amount of heat        would be required to warm the solution until it reaches the        gelation temperature, which raises several potential problems:        -   a) Gelation may occur only slowly or not at all.        -   b) Depending upon the rate of heat transfer from the body            tissues, the temperature of the polymer solution may            increase only very slowly, and it may take an unacceptably            long time to become a gel. For a large volume of polymer            solution, the total amount of heat that can be drawn from            the tissues may be insufficient achieve the gelation            temperature. Particularly in the case of the abdomen, the            amount of heat available is relatively limited since much of            the abdomen is bounded by the abdominal wall, which is            relatively thin and not highly vascularized.        -   c) There is a risk of inducing hypothermia, which could not            only have significant adverse systemic consequences, but may            also compromise the control of hemorrhage by reducing the            ability of the blood to clot.

These deficiencies are addressed by the delivery of the Pluronicsolution as a foam rather than as bulk liquid. The foaming formulationsdescribed herein rely upon the internal, intrinsic cooling effect of theexpanding gas to reduce the temperature of the polymer solution at theinstant it is dispensed. Therefore, it is not necessary to pre-chill thedelivery container or to provide any external means of cooling. This isan important distinction from the prior art relating to Pluronicsolutions which requires the container to be cooled before use in orderto convert the polymer solution to a low viscosity liquid.

The foaming formulations described herein also require a much smalleramount of the Pluronic solution to completely fill the wound or bodycavity than would be needed for a non-foaming solution. As shown in theexamples, a suitable foaming polymer solution can expand at least25-fold after it is dispensed. Consequently, the total heat capacity ofthe foam will be much lower than an equivalent final volume of anon-foaming solution, and therefore the amount of heat absorbed by thefoamed polymer solution will also be proportionately lower. Note alsothat the foam has a thermal insulating effect because it greatly reducesmixing due to convection, which would otherwise occur if the solutionwas in liquid form. The insulating effect will tend to retain the heatin the layer of foam in contact with, or in close proximity to, theinternal surfaces of the cavity, thereby promoting gelation preciselywhere it is required, while slowing the rate of heat transfer to thebulk of the polymer solution.

Examples have been presented herein which demonstrate the features andadvantages of certain synthetic polymer formulations representingembodiments of the invention. These examples are not intended to limitthe scope of the invention to any specific formulations of syntheticpolymers, gases, or volatile liquids and/or concentrations orcombinations thereof. It will be apparent to those skilled in the artthat formulations containing other poloxamers, other synthetic polymers,other expanding gases, and optionally other components includingcompounds intended to build and stabilize the foam may also be used. Itwill also be apparent that agents to assist in the control of hemorrhageor to provide other therapeutic benefits may also be advantageouslyincluded within and delivered by the synthetic polymer formulation.

There have also been illustrated and described herein certain systemsand methods for delivering said synthetic polymer formulations to thebody. While particular embodiments have been described, it is notintended that the invention be limited thereto, as it is intended thatthe invention be as broad in scope as the art will allow and that thespecification be read likewise.

Furthermore, while parts of the embodiments of the invention weredescribed as having certain shapes, and being made of certain materials,it will be appreciated that other materials and shapes can be utilized.For example, it is evident that the system could easily be modified todeliver other therapeutic and/or diagnostic liquids, gases, solutions,and/or suspensions to the body. For another example, it is evident thatthe synthetic polymer formulation could be used to stop bleeding in theabdominal cavity, thoracic cavity, junctionally, externally,intravaginally, intrauterine, intracranially, intranasally, and/or intopuncture or other wounds (e.g. abscess). For areas that are notnaturally a contained space or could have easy spillage from within it(e.g. nares, uterus after delivery), the system may also contain a meansfor blocking exit of the foam from part of the cavity (e.g. aninflatable balloon, packing) to allow for use. It is also evident thatthe synthetic polymer formulation could be inserted into a cavity viaother means (e.g. simple tubing, naked needle, Veress needle, opensurgical approach, direct spray) and that the synthetic polymerformulation could be used without the delivery device or the deliverydevice could be used to deliver other materials. It will therefore beappreciated by those skilled in the art that yet other modificationscould be made to the provided invention without deviating from itsspirit and scope as so claimed.

The following references include information relevant to the devices andmethods of the present invention and are hereby incorporated byreference: Eastridge et al. Death on the battlefield (2001-2011):Implications for the future of combat casualty care. J Trauma Acute CareSurg. 73(6) Sup 5.; and Clarke, J R et al. Time to Laparotomy forIntra-abdominal Bleeding from Trauma Does Affect Survival for Delays Upto 90 Minutes. Journal of Trauma-Injury Infection & Critical Care. 200252(3): p420-425

1. A pressurized therapeutic composition configured to be stored in avalved container designed to maintain the composition under pressure anddispense the composition upon opening the valve thereof, the compositioncomprising a copolymer solution of a copolymer of ethylene oxide andpropylene oxide in an aqueous solution combined with an organicliquefied gas, wherein said organic liquified gas is dissolved in orevenly dispersed throughout the copolymer solution so as to cause thecopolymer solution to foam after the composition is dispensed from thecontainer.
 2. The pressurized therapeutic composition according to claim1 wherein the copolymer has an average molecular mass of about 1 kg/molto about 50 kg/mol, and a mass ratio of ethylene oxide to propyleneoxide of between 25:75 to 95:5.
 3. The pressurized therapeuticcomposition according to claim 1 wherein: the copolymer of ethyleneoxide and propylene oxide is a poloxamer selected from the groupconsisting of: P188, P237, P338 and P407; and the concentration of thepoloxamer in the aqueous solution is between about 25% and about 50%w/w.
 4. The pressurized therapeutic composition according to claim 1wherein: the copolymer of ethylene oxide and propylene oxide ispoloxamer P188; and the concentration of poloxamer in the aqueoussolution is between about 40% and about 50% w/w.
 5. The pressurizedtherapeutic composition according to claim 1, wherein the organicliquified gas comprises between about 2.5% and about 20% of the totalmass of the composition.
 6. The pressurized therapeutic compositionaccording to claim 1, wherein the organic liquified gas is ahydrocarbon.
 7. The pressurized therapeutic composition according toclaim 1, wherein the organic liquified gas is carbon dioxide.
 8. Thepressurized therapeutic composition according to claim 1, wherein theorganic liquified gas is a haloalkane or a blend of haloalkanes.
 9. Thepressurized therapeutic composition according to claim 9, wherein theorganic liquified gas is a hydrofluorocarbon or a blend ofhydrofluorocarbons.
 10. The pressurized therapeutic compositionaccording to claim 10, wherein the hydrofluorocarbon is1,1,1,2-Tetrafluoroethane or a blend of 1,1,1,2-Tetrafluoroethane withother hydrofluorocarbons.
 11. A method for delivering a therapeuticthermoreversible composition to the body, comprising: preparing athermoreversible aqueous polymer solution comprising a suitable polymerat a concentration that will give a predetermined gelation temperature;blending the thermoreversible aqueous polymer solution with a compatibleliquefied gas at a pressure that exceeds the vapor pressure of theliquified gas; transferring the thermoreversible polymersolution/liquified gas blend into a valved container which maintains theblend at a pressure higher than the vapor pressure of the liquified gas;opening the valve on the container, to dispense the thermoreversiblepolymer solution/liquified gas blend; wherein adiabatic expansion of theliquefied gas rapidly cools the thermoreversible polymer solution tobelow the predetermined gelation temperature, causing thethermoreversible polymer solution to change from a highly viscous gel toa flowable liquid while being dispensed, thereby eliminating the need topre-chill the thermoreversible polymer solution before use.
 12. Themethod according to claim 11, wherein the compatible liquefied gas isselected from the group consisting of: nitrous oxide, carbon dioxide,hydrocarbons, and haloalkanes.
 13. The method according to claim 11,wherein the thermoreversible aqueous polymer solution contains a polymerwhich causes the thermoreversible composition to become a foam after itis dispensed.
 14. The method according to claim 13, wherein thethermoreversible aqueous polymer solution contains one or morepoloxamers selected from the group consisting of: P188, P237, P338 andP407; and the total concentration of poloxamers in the aqueous solutionis between about 25% and about 50% w/w.
 15. The method according toclaim 13, wherein the thermoreversible aqueous polymer solution containspoloxamer P188 at a concentration of between about 40% and about 50%w/w.
 16. The method according to claim 11, wherein an apparatus isattached to the valved container to allow the thermoreversiblecomposition to be delivered into a body cavity or a penetrating wound.17. The method according to claim 13, wherein the thermoreversiblecomposition is delivered as a foam into a body cavity or a penetratingwound rather than as a liquid, such that the total amount of the aqueouspolymer solution required to fill the body cavity or penetrating woundwith the thermoreversible composition is significantly reduced.
 18. Themethod according to claim 16, wherein the thermoreversible compositionis delivered as a foam into a body cavity or a penetrating wound ratherthan as a liquid, such that a controllable and measurable positivepressure is exerted by the composition against the surfaces of theorgans within the body cavity or against the tissue surfaces within awound.
 19. The method according to claim 18, wherein the controllableand measurable positive pressure exerted by the composition within thebody cavity or penetrating wound resists the flow of blood from damagedor severed blood vessels to provide a means to control hemorrhage insites which are not amenable to direct physical compression.
 20. Themethod according to claim 18, wherein: the composition exerts acontrollable and measurable positive pressure within the abdomen orpenetrating wound which resists the flow of blood from damaged orsevered blood vessels; and upon contact with the tissue surfaces, thetemperature of the thermoreversible composition increases, causing thecomposition to transform from a flowable liquid into a highly viscousgel which also resists the flow of blood from damaged or severed bloodvessels to provide a means to control incompressible hemorrhage.
 21. Themethod according to claim 18, wherein: the thermoreversible compositionis delivered as a foam into the abdominal cavity; the thermoreversiblecomposition exerts a controllable and measurable positive pressurewithin the abdomen which resists the flow of blood from damaged orsevered blood vessels; and upon contact with the abdominal walls andorgans, the temperature of the thermoreversible composition increases,causing the composition to transform from a flowable liquid into ahighly viscous gel which also resists the flow of blood from damaged orsevered blood vessels to provide a means to control incompressibleabdominal hemorrhage.
 22. A method for controlling hemorrhage inside abody cavity or penetrating wound by delivering a foaming compositioninto said body cavity or penetrating wound, in which; the foamingcomposition is sterile, biocompatible, and substantially chemicallyinert; the foaming composition is provided as a single component that isready to use, and does not need to be either combined with a secondcomponent or cooled by external means before or during delivery to thebody; and the foaming composition does not solidify after delivery butrather forms an aqueous gel which can be easily removed by hand, bysuction, and by rinsing with water or saline, if surgical interventionis subsequently required.
 23. The method according to claim 22 wherein,if surgical intervention is not required; the foaming composition may bepartially or fully removed by peritoneal lavage; or the foamingcomposition may be left in situ to be absorbed or resorbed by the body.24. The method according to claim 22, wherein; the foaming compositioncomprises a thermoreversible aqueous polymer solution blended with aliquified gas; the foaming composition is maintained under pressure insubstantially liquid form until delivered to the body, whereupon adecrease in pressure causes the foaming composition to expand into afoam; and the thermoreversible aqueous polymer solution undergoes aphase change from a flowable liquid to a viscous gel after coming intocontact with the body.
 25. The method according to claim 24, wherein thethermoreversible aqueous polymer solution comprises a polymer that isFDA approved as pharmaceutical excipient and is suitable for delivery ofdrugs and other active therapeutic agents to the body.
 26. The methodaccording to claim 25, wherein the thermoreversible aqueous polymersolution comprises one or more active therapeutic agents to the body.27. The method according to claim 26, wherein the thermoreversibleaqueous polymer solution comprises a procoagulant agent.
 28. The methodaccording to claim 26, wherein the thermoreversible aqueous polymersolution comprises an antibacterial agent.